Download Effect of Excipients on Oxcarbazepine Release from Modified

Journal of Applied Pharmaceutical Science 02 (08); 2012: 150-158
ISSN: 2231-3354
Received on: 11-07-2012
Revised on: 27-07-2012
Accepted on: 13-08-2012
DOI: 10.7324/JAPS.2012.2826
Effect of Excipients on Oxcarbazepine Release from
Modified Release Matrix Tablets
Buchi N. Nalluri, S. Vidyasagar and K. M. Maheswari
ABSTRACT
Buchi N. Nalluri, S. Vidyasagar
and K. M. Maheswari
Department of Pharmaceutics,
K.V.S.R Siddhartha College of
Pharmaceutical Sciences,
Vijayawada-520010, AP, INDIA.
The present investigation was undertaken with an objective of formulating modified
release (MR) matrix tablets of Oxcarbazepine (OXC) an anti-epileptic drug, based on cellulose
ether polymers like Hydroxy Propyl Methyl Cellulose (HPMC K4M and LVCR 100) and
Hydroxy Propyl Cellulose (HPC JF) as drug release retardants to overcome poor patient
compliance and exposure to high doses associated with currently marketed immediate release
(IR) dosage forms. The tablets were prepared by direct compression process and evaluated for
various physico- chemical/mechanical parameters. Among three polymers used, HPMC LVCR
100 is selected as release retardant based on the viscosity and gel formation during dissolution.
The effect of different fillers like Avicel PH 101, Avicel PH 105, Pre gelatinized starch (PGS),
maize starch with spray dried lactose (FLOWLAC) and Di-calcium phosphate (DCP) on OXC
release was also studied and the OXC percent release at the end of 12h is in the order of
DCP>FLOWLAC>Avicel PH 101>Avicel PH 105>PGS. Based on the dissolution data
obtained with different fillers and keeping in view of the results from the pre compression
studies, and gel layer retaining with the matrix tablets, Avicel PH 105 was selected as carrier to
carry out further formulation development. Since, OXC is poorly water soluble drug,
solubilizing agents like surfactants, cyclodextrins and polyethylene glycols were included in
the formulations and their effect on OXC release was studied in order to achieve therapeutic
effective levels. Formulations containing 20% (w/w) of Hydroxy Propyl-β-Cyclodextrin gave
superior OXC release of 85.50 ± 1.62% at the end of 12hours and fulfils the regulatory
requirement. The dissolution data was also evaluated for drug release kinetics and mechanisms.
Keywords: Oxcarbazepine, matrix tablets, cellulose ether polymers, fillers and solubilizing
agents.
INTRODUCTION
For Correspondence
Buchi N. Nalluri
Director for PG Studies and Research,
KVSR Siddhartha College of
Pharmaceutical Sciences,
Vijayawada-520 010, AP, India
Tel: +91-866-2493346
Over the past few decades several new chemical entities (NCEs) have been discovered,
out of which 40% are lipophilic and poorly soluble drugs (Mudit D 2011). Solubility of the drug is
the main obstacle in the delivery of the NCEs and also existing drugs. The ability of improving the
solubility and delivery of poorly soluble drugs is very important step in formulation development.
It can be enhanced through either altering the macromolecular characteristics of the drug particles,
or chemical or mechanical modification of the environment surrounding the drug molecule.
Particle size reduction, addition of surfactant, pH adjustment, self-emulsifying systems and
inclusion in cyclodextrin-drug complexes are the best examples for the solubility enhancement
techniques (Mohanachandran, 2010).
Journal of Applied Pharmaceutical Science 02 (08); 2012: 150-158
Together with the solubility, the permeability behaviour
should also be considered in the development of formulation for
oral administration. Drug absorption from solid dosage forms after
oral administration depends on the release of the drug substance
from the drug product, the dissolution or solubilization of the drug
under physiological conditions, and the permeability across the
gastrointestinal tract. Because of the critical nature of the first two
steps, in vitro dissolution may be relevant to the prediction of in
vivo performance.
OXC (as both mono therapy and adjunctive therapy) has
shown efficacy in the treatment of partial onset seizures with
epilepsy (Tripathi, 2010) and belongs to the category of BCS class
II, and its dissolution is the rate-limiting step for absorption
(Wellington, 2001). OXC is having half-life of 2h and is
completely absorbed and extensively metabolized to its
pharmacologically active 10-monohydroxy metabolite, which has a
half-life of 9h. The maximum dose administered per day is
2400mg and administered 2-3 times in divided doses (Sean, 1999).
Different dosage strengths like 150, 300 and 600mg of immediate
release (IR) tablets are marketed. In the existing dosage form (as
an IR tablet), poor patient compliance and exposure to high doses
of the drug may be anticipated and modified release (MR) dosage
forms are needed for better therapeutic efficacy and patient
compliance. So far no reports were published on CR/MR dosage
forms of OXC. However, some patents on OXC controlled release
formulations were published (Bharat PM 2006, Sankar R 2007,
Jayanta KM 2009, Padmanabh PB 2009). Hence, the present
investigation was aimed to develop twice a day oral MR tablet
dosage forms for OXC based on cellulose ether polymers like
HPMC, HPC as drug release retardants. Since, OXC is poorly
water-soluble drug, its release from the modified release tablets is
incomplete and therapeutically effective drug levels may not be
achieved. So, excipients like surfactants, cyclodextrins and
polyethylene glycols were included in the formulations and their
effect on the OXC release was studied in order to achieve
therapeutically effective levels of OXC from MR tablets.
EXPERIMENTAL
Materials and Methods
OXC (Novartis India Ltd, Mumbai), Hydroxy Propyl
Methyl Cellulose K 100 LV (Colorcon, India), Hydroxy Propyl
Methyl Cellulose K4M (Colorcon, India), Hydroxyl Propyl
Cellulose JF (Aqualon-Herculus, USA), Microcrystalline celluloseAvicel PH 105 (FMC Biopolymers, USA), Microcrystalline
cellulose- Avicel PH 101 (FMC Biopolymers, USA), Pregelatinized starch (Rouette Pharma, France), Maize starch with
Spray dried lactose-FLOWLAC (Rouette Pharma, France), Dicalcium phosphate (Finar, Mumbai), Poly ethylene glycol 6000
(Merck Pvt Ltd, Mumbai), Beta Cyclodextrin (Rouette Pharma,
France), Hydroxy Propyl Beta Cyclodextrin (Rouette Pharma,
France), Sodium lauryl sulphate (Merck Pvt Ltd, Mumbai), Talc
(Finar, Mumbai), Magnesium stearate (Finar, Mumbai)
were used. All the chemicals and reagents are of analytical grade.
Analytical Procedures
Both UV-VIS spectrophotometric method and RP-HPLC
methods were used in the present investigation. UV-VIS
spectrophotometric method (UV-Double Beam Spectrophotometer,
UV-1800, Shimadzu, Japan) based on the measurement of
absorbance at 256nm in a methanol stock solution was used. A
reverse phase HPLC system was used for the analysis of OXC in
different samples. Chromatographic separation was performed on a
Shimadzu Prominence HPLC system equipped with LC 10 AVP
binary pumps, DGU 20A Degasser, M20 A PDA detector and LC
10ATVP auto sampler with 200μL loop volume. LC solution
software was used to collect and process the data. Mobile phase
consisting of 0.02% v/v formic acid: methanol (50:50%) at
1.0mL/min flow rate was used and the mobile phase was filtered
through membrane filter (Millipore Nylon disc filter of 0.45μ) and
sonicated for 3 min in ultrasonic bath before use. Quantification
and linearity were achieved at 229 nm over the concentration range
of 10-50μg/mL and a Phenomenex C18 column (150mm x4.6mm,
5.0µ) was used and separation was carried out at ambient
temperature with an injection volume of 10μL.
Solubility Studies
Excess amounts of OXC (50mg) was added to 15mL of
each fluid in a 25mL stopper conical flask and the mixtures were
shaken for 24 hours at room temperature (28 ± 1C) on rotary
shaker (Remi Rotary Shaker, India). After 24 hours of shaking
1mL aliquots were withdrawn at different time intervals and
filtered immediately using a 0.45µ nylon disc filter. The filtered
samples were diluted suitably and assayed for OXC by above
HPLC method. Shaking was continued until three consecutive
estimations were same. The solubility experiments were run in
triplicate.
Drug excipients compatibility by FT-IR spectroscopy
The FT-IR spectra of pure drug and OXC with different
excipients like HPMC K4M, HPMC LVCR 100, HPC JF, Avicel
PH 105, Avicel PH 101, PGS, FlowLac, DCP, SLS, PEG 6000, βCD and HP- β- CD was measured using ATR-FTIR
spectrophotometer (Bruker, Germany). ATR spectra were
measured over the wave number range of 4000-500 cm-1 at a
resolution of 1.0 cm-1. The powder or film sample is simply placed
onto the ATR crystal and the sample spectrum is collected.
Preparation of OXC MR Tablets
OXC MR tablets were prepared by direct compression
method, as per formulae given in Table 1. HPMC K4M, HPMC
LVCR 100 and HPC-JF were used as release retardant materials.
Sufficient quantities of MCC (Avicel PH 101 and PH 105), pre
gelatinized starch, maize starch and spray dried lactose and dicalcium phosphate were used to raise the bulk volume of the
tablets to a weight of 400mg each. Talc and magnesium stearate at
0.5% w/w levels were used as glidant/lubricants. All the
ingredients were passed through sieve # 80 before mixing. In case
of PEG 6000 fraction of sieve# 100 was used.
Journal of Applied Pharmaceutical Science 02 (08); 2012: 150-158
Table. 1: Formulae of MR tablets of OXC with different excipients.
Ingredients
OXC
HPMC K4M
HPMC LVCR 100
HPC JF
Avicel PH 105
DCP
Avicel PH 101
Pre gelatinized
starch
FlowLac
SLS
PEG-6000
β-CD
HP-β-CD
Magnesium stearate
Talc
Total
F1
150
80
166
2
2
400
F2
150
80
166
2
2
400
F3
150
80
166
2
2
400
F4
150
80
166
2
2
400
Initially drug and polymers were mixed thoroughly and then
required quantities of fillers were added and finally the blend was
mixed with talc and mixed thoroughly for 5min in a poly bag and
then added the required amount of magnesium stearate and mixed
for another 5 min. Powder blends (for 50 tablets each) of all the
above formulations were compressed on single punch tablet press
(Cadmach, India) using 10 mm punches (round shape) to a
hardness of 4-6 kg/cm2.
Evaluation of Flow Properties of powder blend
The powder blends were evaluated for parameters like
bulk density, tapped density, Carr’s index, Angle of repose, and
Hausner’s ratio (United State Pharmacopoeia 2007).
Evaluation of OXC MR Tablets
The compressed MR tablets were evaluated for following
properties: drug content, uniformity of weight, friability, hardness,
and disintegration time and in vitro drug release profiles (Lachman,
1987).
Drug content
Ten tablets were weighed and powdered in a mortar.
Accurately weighed tablet powder samples equivalent to 20mg of
OXC was transferred to a 100mL volumetric flask, and the OXC
was extracted into 75mL methanol and then finally the volume was
made to 100 mL with methanol. This solution was filtered through
0.45µ nylon disc filter and the filtrate was suitably diluted with
methanol and the samples were analyzed by HPLC. The
estimations were carried out in triplicate.
Uniformity of weight of tablets
The individual and total weight of 20 tablets from each
batch was determined. Percentage deviation of the individual
weights from the average weights was calculated.
Hardness
The hardness of the tablets was measured with a
Monsanto hardness tester (M/s Campbell Electronics, model EIC-
Formulations (Amounts in mg)
F5
F6
F7
F8
150
150
150
150
80
80
80
80
126
166
166
166
40
2
2
2
2
2
2
2
2
400
400
400
400
F9
150
80
126
40
2
2
400
F10
150
80
106
60
2
2
400
F11
150
80
86
80
2
2
400
F12
150
80
106
60
2
2
400
F13
150
80
86
80
2
2
400
66, India). The results reported were average of 6 tablets for each
formulation.
Friability
For each formulation 10 tablets were weighed, placed in
Friabilator (M/S Cambell Electronics, India) and were subjected to
100 rotations in 4min. The tablets were reweighed and friability
was
calculated
by
the
following
formula:
Friability 
W 2 W1
 100
W1
Where W1 is the initial weight and W2 is the final weight of the
tablets.
In vitro Dissolution studies
In vitro dissolution studies of MR tablet formulations
prepared were carried in 900 mL of 0.1N HCl with 0.25% w/v SLS
as dissolution medium using USP XXI type II (Paddle method)
Dissolution Rate Test Apparatus.(LABINDIA, DS 8000) at 50
rpm. The temperature was maintained constant at 37±0.5°C. 5 mL
aliquots were withdrawn at different time intervals and filtered
using a 0.45µ nylon disc filters and replaced with 5mL of fresh
dissolution medium. The filtered samples were suitably diluted if
necessary and assayed for OXC by HPLC method. The dissolution
experiments were conducted in triplicate.
Release kinetics and mechanism
Different kinetic models i.e., zero-order (Brazel, 2000)
first-order (Lapidus, 1966), Higuchi’s (Higuchi, 1963), and release
mechanism model Korsmeyer Peppas (Korsmeyer, 1983) were
applied to interpret the release profile of OXC from matrix
systems. Due to the differences in drug release kinetics, the Peppas
constant k, though is one of the measures of release rate, should not
be used for comparison. Therefore, to characterize the drug release
rate in different formulations, mean dissolution time (MDT) was
calculated from dissolution data using the formula: MDT = (n/n+1)
× k-1/n, where n is the release exponent and k is the Peppas constant
(Mockel JE 1993). MDT value is used to characterize the drug
release rate from the dosage form and the retarding efficacy of the
Journal of Applied Pharmaceutical Science 02 (08); 2012: 150-158
polymer. A higher value of MDT indicates a higher drug retarding
ability of the polymer and vice-versa (Hamzaha, 2010).
RESULTS AND DISCUSSION
OXC is not yet official in any pharmacopoeia; official
dissolution rate test is not available. However, dissolution rate tests
were reported where 0.1N HCl with 0.25% w/v SLS was used as
dissolution medium for evaluating the in vitro dissolution profiles
of IR OXC formulations (Nirav P 2008). Based on the published
reports, the solubility of OXC in 0.1N HCl with 0.25% w/v SLS,
0.1N HCl with 0.5% w/v SLS, 0.1N HCl with 1% w/v SLS and
distilled water were carried out and the results were shown in
Figure 1. An increase in SLS concentration increased the OXC
solubility in 0.1N HCl. A 3.32-fold increase in OXC solubility
with 0.5% w/v SLS in 0.1N HCl was observed when compared to
without SLS and the solubility of OXC increased with increasing
the SLS concentration. Based on the data of the solubility studies
and keeping in view of the discriminating power of the selected
dissolution medium and excipients selected in the formulation
development studies all the dissolution experiments were carried
out in 0.1N HCl with 0.25% w/v SLS as dissolution medium.
Fig. 1: Solubility of OXC in different fluids.
Drug excipient compatibility study
FTIR studies were carried with a view to evaluate the in
situ drug and excipient/s compatibility. Figure 2 shows the IR
spectra of pure OXC and OXC with different excipients. Pure
OXC showed characteristic IR absorption bands at 3334 cm-1 for
the N-H group bending, 1645 cm-1 for the C=O stretching. The
absorption bands at 1556 cm-1 were denoted for stretching
vibrations of C=C in aromatic ring. These characteristic IR
absorption bands of OXC were all retained in the presence of the
selected excipients indicates that there is no interaction between
the OXC and excipients.
Determination of pre and post compression parameters
The results of various pre compression parameters are
given in Table 2. These results indicate that the powder blends of
all formulations are suitable to prepare tablets by direct
compression technique. The compressed tablets fulfilled the
official compendial requirements regarding drug content,
uniformity of weight, hardness and friability. The results are given
in Table 3.
In Vitro Dissolution Studies
All the tablet formulations were subjected to in vitro drug
release studies using 0.1N HCl with 0.25% w/v SLS as dissolution
medium, in order to assess drug release profiles including release
kinetics and drug release mechanisms from tablets. In the present
investigation swellable polymers like HPMC K4M, HPMC LVCR
100 and HPC-JF were used to retard the OXC release from the MR
tablets.
Initial formulation studies were carried out to look in to
the release retarding effect of different swellable polymers like
HPMC K4M, HPMC LVCR 100 and HPC JF at a level of 20%w/w
in the formulations (F1-F3) using AVICEL PH 105 as filler. The
release profiles were shown in Figure 3. All the polymers gave a
controlled release pattern over a period of 12h, as these polymers
swelled upon contact with the dissolution media and a gel layer
was formed on their surface. This gel layer retarded further ingress
of fluid and subsequent drug release. F1 containing OXC and
HPMC K4M released lesser amount of drug (29.66 ± 1.01) at the
end of 12h. This low percent of drug release is due to the higher
viscosity of the polymer. F2 containing OXC and HPMC LVCR
100 released an amount of 48.87 ± 2.10 at the end of 12h, whereas,
the F3 gave 67.76 ± 3.10 OXC release at the end of 12h. However,
with the F3 containing HPC JF as release retardant material, no gel
layer was formed but the tablets were slowly and completely
eroded at the end of 12h. A good gel layer was observed with the
F1 and F2 and the more swelling was observed with the F2
containing HPMC LVCR 100 and is because of low viscosity of
the polymer and is a good candidate as a drug release retardant for
poorly water soluble drugs like OXC. Based on these results and
on MDT values (Table 4) obtained, and the solubility of the OXC,
the studies were further carried out using HPMC LVCR 100 as a
release retardant material.
Diluents fill out the size of a tablet or capsule, making it
practical to produce and convenient for the consumer to use.
Diluents slightly affect the drug release from dosage form. Among
the various water soluble and insoluble and directly compressible
grade diluents, few diluents such as, AVICEL PH 101 and 105,
PGS, maize starch with spray dried lactose (FLOWLAC) and DCP
were used in studies to further formulate MR matrix tablets and
their effect on OXC release was studied. F4-F7 were developed
using AVICEL PH 101, PGS, FLOWLAC (maize starch with
spray dried lactose) and DCP respectively. The comparative OXC
release profiles were shown in Figure 4. F4 containing AVICEL
PH 101 as filler gave 54.78 ± 3.30 percent drug release at the end
of 12h and is higher than the AVICEL PH 105 (F2). Initial burst
release at 1 h is 11.31 ± 1.15 and 6.78 ± 1.12 respectively for F4
and F2. Superior burst release was achieved with F4 containing
AVICEL PH 101 as filler. This could be due to the quicker
swelling of the formulation when compared to F2. Further trials
Journal of Applied Pharmaceutical Science 02 (08); 2012: 150-158
were carried out using PGS as filler (F5) and the release profile
was shown in Figure 4. The percent release at the end of the 12h is
38.87 ± 4.01. The slower drug release observed with pre
gelatinized starch is may be due to the increased viscosity of gel
layer and decreased penetration of dissolution medium towards the
matrix core. This result was further confirmed by the higher MDT
value of 461.93 min (Table 4). While, the formulation (F6)
containing water soluble filler maize starch with spray dried
lactose showed higher release of 66.39 ± 2.12% at the end of 12h.
The increase in release is may be due to solubility of filler in the
dissolution medium and thereby making channels in gel matrix.
This also leads to deformation of the matrix shape in the
dissolution medium and results the erosion of matrix in dissolution
medium. Further, DCP was used as filler (F7) and resulted in 71.73
± 3.03% release at the end of 12h. The release profiles were shown
in Figure 4. This higher release of OXC is may be due to the
erosion of the tablet in the dissolution medium. Hence, based on
the dissolution data obtained with F4-F7 and keeping in view of
the results from the pre compression studies, and gel layer
retaining with the matrix tablets the Avicel PH 105 was selected to
carry out the further formulation development.
Since, OXC is poorly water-soluble drug, its release from
the MR tablets is incomplete and therapeutically effective drug
levels may not be achieved for a MR dosage form. The obtained
drug release profiles with F1-F7 explain this fact i.e. only between
29-71% of OXC release was obtained with all these formulations.
Hence, excipients in the category of solubilizing agents, like
surfactants (SLS), complex forming agents (cyclodextrin like β-CD
and HP-β-CD) and solubilizing and channeling agents (PEG 6000)
at levels of 10-20% w/w of the total tablet weight were included in
the formulations and their effect on the OXC release was studied in
order to achieve therapeutically effective levels of OXC.
Surfactants are commonly used in pharmaceutical dosage
forms as wetting agents. SLS is an anionic and water-soluble
surface active agent. It can be used effectively as a wetting agent in
both alkaline and acidic conditions. SLS has been used in
A
Fig. 2: continues….
quantities of 10% w/w of total tablet weight for its surface tension
lowering capability and to improve dissolution of poorly soluble
drugs like OXC. Formulation containing SLS 10% (F8) showed
72.39 ± 4.32% release at the end of 12h and the increase in OXC
release is may be due to enhancement of wettability of OXC by the
SLS there by solubility within the matrix gel. The release profiles
were shown in Figure 5. In another trial PEG 6000 at 10% w/w
total tablet weight was incorporated in the formula (F9) and a good
drug release (80.98 ± 1.65%) was observed with formulation
containing PEG 6000 at the end of 12h. Increase in drug release is
due to the solubilizing effect of PEG 6000 on OXC within the
matrix gel and also the channeling effect by PEG within the matrix
gel, there by more diffusion of solubilized OXC from the core. The
release profiles were shown in Figure 5. Further formulations were
developed with cyclodextrins at levels of 15% and 20% w/w of the
total tablet weight (F10, F11, F12, and F13). Cyclodextrins are
cyclic oligosaccharides with a hydrophilic outer surface and a
hydrophobic central cavity. In aqueous solutions, cyclodextrins can
form inclusion complexes with lipophilic drugs by entrapping the
non polar part of it inside the hydrophobic cavity. A 79.67 ± 2.85
% and 84.18 ± 1.14 % OXC release was observed with F10 and
F11 containing β-CD at 15 and 20% w/w levels respectively at the
end of the 12h. The release profiles were shown in Figure 5. An
82.27 ± 0.73 % and 85.50 ± 1.62 % OXC release was observed
with F12 and F13 containing HP-β-CD at 15 and 20% w/w levels
respectively at the end of the 12h. The release profiles were shown
in Figure 5.
Overall, increase in the cyclodextrins levels increased the
OXC release from the tablets. The OXC release was more with
HP-β-CD when compared to the β-CD. This is because of the more
hydrophilic nature of HP-β-CD than the β-CD. Among the all the
formulations, F13 containing 20% w/w HP-β-CD gave superior
and required OXC release of 85.50 ± 1.62 % at the end of 12h and
fulfils the regulatory requirements in terms of percent drug release
(i.e. not less than 85% at the end of the time points for modified
release dosage forms).
B
Journal of Applied Pharmaceutical Science 02 (08); 2012: 150-158
C
D
F
E
G
Fig. 2: continues….
H
Journal of Applied Pharmaceutical Science 02 (08); 2012: 150-158
J
I
K
L
M
Fig. 2: FTIR spectra of (A) pure OXC, (B) OXC-HPMC K4M, (C) OXC-HPMC LVCR 100, (D) OXC-HPC JF, (E) OXC-Avicel PH105, (F) OXC-Avicel PH101(G)
OXC- PGS (H) OXC-FLOWLAC (I) OXC-DCP (J) OXC- SLS, (K) OXC- PEG 6000, (L) OXC-β-CD, (M) OXC-HP- β-CD.
Journal of Applied Pharmaceutical Science 02 (08); 2012: 150-158
Fig. 3: Comparative dissolution profiles of F1-F3
Fig. 4: Comparative dissolution profiles of F4-F7
Fig. 5:Comparative dissolution profiles of F8-F13
Table. 2: Pre compression parameters of tablet powder blend.
Formulation
Bulk density (g/mL)
Tapped density (g/mL)
F1
0.336
0.252
F2
0.331
0.257
F3
0.399
0.258
F4
0.319
0.233
F5
0.329
0.243
F6
0.345
0.262
F7
0.342
0.249
F8
0.353
0.256
F9
0.339
0.253
F10
0.332
0.251
F11
0.319
0.248
F12
0.324
0.254
F13
0.325
0.251
Table. 3: Various evaluation parameters of OXC MR tablets.
Formulation
Drug content (mg/tab)
F1
149.2
F2
149.8
F3
151.4
F4
150.3
F5
149.4
F6
150.6
F7
149.2
F8
149.2
F9
150.8
F10
149.4
F11
149.1
F12
148.9
F13
149.5
Compressibility index (%)
33.3
28.7
42.9
41.2
35.3
31.6
37.3
37.8
33.9
32.2
28.6
27.5
29.4
Weight variation (mean ± SD)
398 ± 2.4
398 ± 3.2
399 ± 1.2
399 ± 2.4
401 ± 2.3
402 ± 2.1
398 ± 2.2
397 ± 3.2
398 ± 2.9
397 ± 1.6
398 ± 1.8
398 ± 1.9
403 ± 2.1
Hausner ratio
1.33
1.34
1.39
1.36
1.35
1.31
1.37
1.37
1.33
1.32
1.28
1.27
1.29
Hardness (kg/cm2)
5
5
5
5
5.5
5
5.5
4.5
5
5
4.5
5
5
Angle of repose (°)
28.6
27.5
34.2
31.1
30.5
28.1
27.9
29.8
30.4
29.5
30.5
28.3
29.9
Friability (% wt. loss)
0.62
0.52
0.56
0.41
0.69
0.52
0.57
0.71
0.59
0.51
0.66
0.72
0.54
Journal of Applied Pharmaceutical Science 02 (08); 2012: 150-158
Table 4. Release kinetic parameters for OXC MR formulations
Zero order
First order
Formulations
K0
R2
K
R2
F1
2.26
0.948
0.025
0.967
F2
3.42
0.947
0.046
0.905
F3
5.34
0.983
0.085
0.935
F4
4.02
0.976
0.058
0.964
F5
3.05
0.987
0.368
0.994
F6
5.37
0.969
0.875
0.996
F7
5.30
0.947
0.090
0.834
F8
5.33
0.971
0.092
0.916
F9
6.09
0.924
0.117
0.823
F10
6.37
0.946
0.122
0.952
F11
6.89
0.981
0.147
0.983
F12
7.08
0.962
0.159
0.994
F13
6.88
0.960
0.143
0.992
Drug release kinetics and mechanisms
The R2 values for F1, F5, F6, F10-13 obtained with first
order plots were found to be superior when compared to the R2
values obtained with zero order plots. These results indicating that
the OXC release from F1, F5, F6, and F10-13 followed first order
kinetics (Table 4).
In case of F2, F3, F4, F7, F8, and F9 the R2 values
obtained with zero order plots were found to be superior when
compared to the R2 values obtained with first order plots. These
results indicating that the OXC release from F2, F3, F4, F7, F8,
and F9 followed zero order kinetics. The Higuchi square root
model showed higher correlation coefficient values (0.807-0.996)
and diffusion is the release mechanism for OXC from the tablets.
The graphs of Log % Qt versus log t showed a linear relationship
with R2 values ranged from 0.852-0.999 and ‘n’ values from 0.570.80 and indicates anomalous transport is the release mechanism
except with the F3 where ‘n’ value is 0.95, indicates the super case
II transport.
Formulations containing different excipients from F8-F13
gave ‘n’ values in the range of 0.5-0.8 indicates the drug release
mechanism with these formulation is because of swelling and
diffusion (anomalous transport). OXC release profiles of these
formulations confirm this fact.
CONCLUSIONS
Overall, HPMC LVCR 100 at 20% w/w level as release
retardant polymer and AVICEL PH105 as filler (F2) was selected
as core formulation and in the absence of HP-β-CD, F2 gave 48.87
± 2.10 % OXC release at the end of 12h and with 20% w/w HP-βCD gave superior and required OXC release of 85.50 ± 1.62 % at
the end of 12h and fulfill the regulatory requirements in terms of
percent drug release.
ACKNOWLEDGEMENTS
The authors are thankful to Novartis India Ltd for
providing the OXC sample and to the Siddhartha Academy of
General and Technical Education, Vijayawada, for providing
facilities to carry out the research work.
Higuchi
KH
4.13
14.50
23.57
16.52
12.76
22.45
22.81
22.16
26.13
27.19
29.22
29.98
29.37
Peppas
R2
0.996
0.876
0.941
0.938
0.977
0.993
0.853
0.907
0.807
0.946
0.987
0.988
0.990
n
0.576
0.713
0.959
0.610
0.640
0.683
0.757
0.579
0.719
0.662
0.716
0.734
0.803
R2
0.992
0.962
0.987
0.969
0.983
0.994
0.941
0.957
0.852
0.939
0.990
0.992
0.999
MDT (min)
543.60
422.00
490.00
309.78
461.93
293.00
312.43
222.21
257.40
235.95
246.23
261.82
286.87
REFERENCES
Bharat PM, Rajen S. Bilayer tablets of Oxcarbazepine for
controlled delivery and a process of preparation. 2006; US
2006/0141037A1.
Brazel CS, Peppas NA. Modelling of drug release from
swellable polymers., Eur.J.Pharm.Biopharm., 2000;49: 47-58.
Hamzaha M, Othman A. Al-Hanbali, Reema K, Ashok K.
Shakya, Anwar M. Testing lyoequivalency for three commercially
sustained release tablets containing Diltiazem hydrochloride, Acta
Poloniae Pharmaceutica - Drug Research, 2010; 67 (1): 93-97.
Higuchi T, Mechanism of sustained action medication,
theoretical analysis of rate of release solid drugs dispersed in solid
matrices. J.Pharm.Sci. 1963; 52: 1145-1148.
Jayanta KM, Nitesh N Controlled release formulation
comprising anti- epileptic drugs. 2009; US 2009/0196923A1.
Korsmeyer RW, Gurny R, Doelker EM, Buri P, Peppas NA.
Mechanism of solute release from porous hydrophilic polymers. Int J
Pharm. 1983; 15:25-35.
Lapidus H, Lordi N. G. Drug release from compressed
hydrophilic matrices, J.Pharm.Sci., 1966; 55: 840-843.
Leon Lachman, Herbert A. Lieberman, Joseph L. Kanig, The
Theory and Practice of Industrial pharmacy, 3rd Edition, Varghese
publishing house, 1987; 296-300.
Martindale-The Complete drug reference, Sean CS 33rd Edition.
Pharmaceutical Press; London, 1999; 354.
Mockel JE, Lippold BC. Zero order release from
hydrocolloidmatrices. Pharm Res. 1993; 10:1066-1070.
Mohanachandran PS, Sindhumol P.G, Kiran T.S. Enhancement
of solubility and dissolution rate: an overview, Int. J. Comp. Pharm, 2010;
4 (11): 1-10.
Mudit D, Ashwini GK, Kulkarni P.K. Enhancement of solubility
and dissolution rate of poorly water soluble drug by spray drying using
different grade of Chitosan, Int. J. Pharm & Pharm Sci. 2011; 3(2): 231235.
Nirav P, Narendra C, Jayvadan P, Tejal S, Julan D, Rajnikant P.
Comparison of In vitro Dissolution profiles of Oxcarbazepine- HP-β-CD
formulations with marketed Oxcarbazepine tablets, Dissolution
Technologies, 2008; 28-34.
Padmanabh PB, Argaw K. Modified release preparations
containing Oxcarbazepine and derivatives. 2009; US 2009/0004263A1,
Sankar R, Narayanan. Sustained release dosage forms of
Oxcarbazepine. 2007; US 2007/0059354A1.
The United State Pharmacopoeia, USP30-NF-25, Asian edition.
Rockville M, United State Pharmacopoeial Convention Inc., 2007, 643645.
Tripathi KD- Essentials of Medical Pharmacology, 6th Edition.
Jaypee Brothers Medical Publishers (p) Ltd.; New Delhi, 2010; 406.
Wellington K, Goa KL. Oxcarbazepine: An update of its
efficacy in the management of epilepsy. CNS Drugs, 2001; 15(2): 137163.